title: p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys(118) acetylation.
abstract: Myocardial infarction, an irreversible cardiac tissue damage, involves progressive loss of cardiomyocytes due to p53-mediated apoptosis. Oxygenation is known to promote cardiac survival through activation of NOS3 gene. We hypothesized a dual role for p53, which, depending on oxygenation, can elicit apoptotic death signals or NOS3-mediated survival signals in the infarct heart. p53 exhibited a differential DNA-binding, namely, BAX-p53RE in the infarct heart or NOS3-p53RE in the oxygenated heart, which was regulated by oxygen-induced, post-translational modification of p53. In the infarct heart, p53 was heavily acetylated at Lys(118) residue, which was exclusively reversed in the oxygenated heart, apparently regulated by oxygen-dependent expression of TIP60. The inhibition of Lys(118) acetylation promoted the generation of NOS3-promoting prosurvival form of p53. Thus, oxygenation switches p53-DNA interaction by regulating p53 core-domain acetylation, promoting a prosurvival transcription activity of p53. Understanding this novel oxygen-p53 survival pathway will open new avenues in cardioprotection molecular therapy.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Gogna
authors.forename: Esha
authors.initials: E
authors.lastname: Madan
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Uttam
authors.initials: U
authors.lastname: Pati
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D008239:Lysine; D010100:Oxygen
keywords: NOS3; lysine acetylation; myocardial infarction; oxygenation; p53